Download Bhangoo-Research-T1DM-and-T2DM

Research & Development
Type 1 & Type 2 Diabetes
Amrit Bhangoo, MD
Division of Pediatric Endocrinology
Children’s Hospital Orange County
May 14th, 2016
Diabetes Mellitus in USA
• Diabetes affects 25.8 million people
• (#1.25 million type1 - 1:4000)
• 8.3 % of US population has diabetes
• If current trends continue, 1 of 3 U.S. adults
will have diabetes by 2050
• Total estimated diabetes type 1 related cost
is $14 billion, 174 billion for all diabetes
http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011
JDRF website
Monitoring glycemic control: early history
From appearance, color,
sediment and often taste
In 1954 Glucotest/Testape roll
1960’s the “dipstix”
Insulin delivery
NovoPen Echo®
Insulcheck
Quest for Cure of Diabetes
• Biological cure
•
•
•
•
Islet cell transplantation
Stem cell development
Immunomodulation
BCG
• Technological Cure
• Hybrid approach
The Natural History of Type 1 Diabetes
Inductive Event
eg. Coxsackie virus
Islet
Cell
Mass
Genetic Predispositions
HLA-DR/DQ
? A.B.C
VNTR INS.
CTLA-4
Others
Islet Antigens
IAA, GAD65A, IA2A, IA-2bA,
Cell Mediated
Glima-38A
response to islet
antigens
Metabolic
Derangements
FPIR to IVGTT
Impaired OGTT
Elevated fasting
glucose
Diabetes Onset
IL-12 / INF-g
Lack of environmental
protection from NK-T
cells / CD25+ T cells
Honeymoon
Phase
9 months – 3 years
months to years
6
months
Immunotherapy
AntiCD3 monoclonal antibody (mAb)
 Otelixizumab
 Low doses did not change c-peptide, HbA1c, insulin dose
and glucose
 Only beneficial in high doses
 Adverse effects
 Teplizumab
 Patients were still insulin dependent
Expert Opin Biol Ther. 2016 Jun;16(6):841-6. doi: 10.1080/14712598.2016.1180363.
Diabetes Care. 2014 Oct;37(10):2746-54. doi: 10.2337/dc13-0327. Epub 2014 Jul 10.
Lancet. 2011 Aug 6;378(9790):487-97. doi: 10.1016/S0140-6736(11)60931-8. Epub 2011
Jun 28.
Oral Insulin - Prevention
 Genetically susceptible to type 1 diabetes
 CD4+ T-cell proliferative responses
 Autoantibodies to GAD-65 or IA2 antigen
 Diabetes Prevention Trial of Type 1 (DPT-1) -Phase 3
 Trialnet Oral Insulin study
 Pre-Pilot study
Newly diagnosed – Stem cell
therapies
 Multipotent mesenchymal stromal cells (MSCs)
 Adult stem cells residing in bone marrow, adipose tissue,
umbilical cord blood
 Migrate to injured areas
 Tissue generation
 T1D-MSCs were able to reverse hyperglycemia in murine
diabetes models
 Lowered ICA, GAD-65 and insulin antibodies of 2 patients
in 12 months
Stem Cell Res Ther. 2016 Jan 18;7:14. doi: 10.1186/s13287-015-0261-, Med Sci
Monit 19:852-857, 2013..
Stem cell / MSCs Drawbacks
 Mild therapy
 “homing” factors toward pancreas
 Pulmonary first pass effect
 Contamination
 Tumorigenicity and immunogenicity
 Cost-effectiveness
Generation of stem cell-derived βcells from patients with type 1
diabetes
 Stem cell-derived β-cells from type 1 diabetic patients
can be used for treatment of diabetes
 β cells in vitro
 Secrete quantities of insulin comparable to adult β
cells
 response to multiple sequential glucose challenges in
vitro
Nat Commun. 2016 May 10;7:11463. doi: 10.1038/ncomms11463
Cell. 2014 Oct 9;159(2):428-39. doi: 10.1016/j.cell.2014.09.040
Islet Cell Technology
• Islet cell encapsulation
• Natural means, e.g., seaweed
• Artificial membranes
• Trying to eliminate the need for chronic
immunosuppressant therapy
• Implantable cell therapy - UCSD conducting
First ever clinical trial of a stem cell-derived
therapy
Clinical Islet Transplantation (CIT)
Consortium
University of Miami
Miami, Florida
University of Minnesota
Minneapolis, Minnesota
University of Pennsylvania
Philadelphia, Pennsylvania
Emory University
Atlanta, Georgia
Northwestern University
Chicago, Illinois
University of Alberta
Edmonton, Alberta, Canada
University of California
San Francisco, California
University of Illinois at Chicago
Chicago, Illinois
University of Wisconsin
Madison Wisconsin
Uppsala University
Uppsala, Sweden
University Hospital Rikshospitalet
Oslo, Norway
Karolinska University
Stockholm, Sweden
Massachusetts General Hospital
Boston, Massachusetts
Collaborative Islet Transplant
Registry Data 2010





571 pancreatic islet allo-transplants
90 with kidney transplant
One or two infusions of islets
Average number of islets received per infusion was 463,000.
1st year - 60 % insulin independence (no insulin for at least 14
consecutive days)
 2nd year - 50 % insulin independence
 Better outcome
 age—35 years or older
 lower pre-transplant triglyceride, or blood fat, levels
 lower pre-transplant insulin use
Collaborative Islet Transplant Registry seventh annual report. Collaborative Islet
Transplant Registry website. Updated December 30, 2011. Accessed July 23, 2013.
ViaCyte Inc - Pancreas in a Capsule
Encapsulation Research
Phase 1/2 trial called STEP ONE, or Safety, Tolerability, and Efficacy of VC-01
Combination Product in Type One Diabetes.
UCSDSchool of Medicine, in partnership with ViaCyte, Inc
Technological “Cure”
 Self Monitoring & Self Management of Diabetes
Blood Glucose Meters
iBG Star meter/app
(Sanofi Aventis,
available)
OneTouch® Verio®Sync
Accu-Chek ® Aviva Expert
Bolus Advisor System
LG KP8400 cell phone (Korea,
2002);
Infopia LG Glucophone/JVAGO
5965 (US, 2008)
Freestyle InsuLinx
(Abbott)
Continuous Subcutaneous Glucose Monitoring
The first Glucose Sensors
Glucowatch Biographer
FDA approval 2001 -2007
Reverse iontophoresis
Cyngnus/Animas
Freestyle navigator
2008 -2011
CGM Gold
Enzyme tipped catheter
1999
Medtronic Guardian
Real time
2004
Dexcom STS 2006
How Does CGM Work?
 Glucose in the interstitial fluid hits the sensor
causing an glucose-oxidation reaction to
occur
Sensor Glucose (SG) vs. Blood
Glucose(BG)
 During rapid states of change, SG and BG may differ
more than 20%
 The CGM needs calibrations a minimum of twice a day
(once every 12 hours)
Todays Glucose Sensors – U.S.
CGM Parts
Enlite
 Sensors
 Transmitters
 Receivers
 Inserters
Dexocm
Sensor Sites
 Change every 6-7 days, per manufacturer guidelines
 Discuss with your healthcare provider if sites can be worn for
longer periods of time
 Check sites daily and remove if reddened, inflamed and/or
irritated or infected
 Adhesive wipes (Skin Tac, IV Prep) and tapes (Tegaderm, IV
3000) may be helpful to keep the sites
 For pain with insertion, try numbing with EMLA/Lidocaine
cream or the Synera patch – ask MD/NP for prescription
Dexcom Share and Dexcom
G5
 Dexcom receiver that has Share blue-tooth capability builtin so you will not have to have a cable and phone attached
to receiver
 Must have iPhone, iPod touch, or iPad with internet
connection close to Dexcom receiver
 Dexcom Share app
 Real-time data available to 5 users on their iPhone, iPad or
iPod touch
Sensor Glucose vs. Meter Glucose
mean absolute relative difference
(MARD)
 Meter MARD


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

FreeStyle Lite
FreeStyle Freedom Lite
Accu-Chek Aviva
Contour
OneTouch UltraEasy
4.9%
5.5%
6.8%
9.0%
9.7%
 Sensor MARD
 Dexcom
 Enlite 2
<10%
13-17%
J Diabetes Sci Technol. A comparative effectiveness analysis of three continuous
glucose monitors: the Navigator, G4 Platinum, and Enlite.2014 Jul;8(4):699-708
Accuracy Evaluation of Five Blood Glucose Monitoring Systems Obtained from the
Pharmacy: A European Multicenter Study with 453 Subjects. 2012 Apr; 14(4): 330–
337
MiniMed Connect
 MiniMed Connect is available for iPhone® or iPod touch®. If you
have a MiniMed® 530G or a MiniMed Paradigm® RevelTM insulin
pump
 Friends and family can view online with CareLink®
Glucose Sensors (contd.)
Navigator Libre – Approved in Europe
Glucose
Tattoo
Medtronic & Ford Motor Company
glucose monitoring on the go
Future Non invasive glucose monitoring
Symphony® CGM
Needle free transdermal sensor
GlucoTrack Ear Lobe Meter
(Approved in Europe 2009, awaiting FDA
approval)
Non invasive glucose monitoring
OrSense: Occlusion near
infrared spectroscopy
First Combined Glucose Sensor and
Insulin Infusion Set
• Combined infusion set and
sensor electrode
®
• MiniMed Duo(TM)
launched in Europe in June
2014.
Insulin Pumps
Tandem’s t:slim pump
FDA approved spring 2012
Asante Solutions’ Pearl/Snap Pump
FDA approved May 2011
Now Bigfoot
OmniPod
Insulin Pump Comparison
Starting
Minimum Basal
Rate
(units/hour)
Reservoir
Volume (units)
Linked
Meter/Remote
Medtronic
Revel/Medtronic 530G
Animas
Ping/Animas Vibe
Tandem tslim/t:slim G4
0.025
0.025 increments
0.025
0.025 increments
0.100
0.01 increment
>0.1unit/hour
0.05
0.05 increments
180 or 300
200
300 or 450 (t-Flex)
(minimum fill is 100 units)
No
200
(minimum fill is 85 units)
Meter/Remote uses Freestyle
strip
Linked meter – Bayer Contour Next Meter/Remote One Touch
Link
Ping
No meter/remote with Vibe
CGM
Yes
No CGM with Ping
Integration
Enlite sensor and Low Threshold
Yes, Vibe integrated with
Suspend with 530G only
Dexcom G4 CGM
Battery
1 AAA, meter is charged via USB
1 AA (can use lithium) for
pump, 2 AAA for Ping
meter/remote
Waterproof
Protected against water immersion waterproof, 12’ for 24
hours; meter/remote not
waterproof
Max Bolus
25
35
Downloading at Carelink (web-based)
Diasend (web-based)
home
Tubeless/Infusi Not tubeless; variety of sets,
Not tubeless; variety of sets,
on Sets
tubing and cannula lengths
tubing and cannula lengths
Omnipod
No CGM with t-slim
No
Yes, t-slim G4 integrated
with Dexcom G4 CGM
Must charge 10-15 min daily 2 AAA
via USB
Watertight
Pod is waterproof; PDM is not
waterproof
25/ T-Flex 60
T-Connect(web-based)
30
Omnipod Partner (web-based)
Not tubeless; variety of
types, tubing and cannula
lengths
Pod – one size only
Only Tubeless pump
Medtronic’s 670G
Phase 3 Clinical Trial
 “hybrid-closed loop” system with
Enlite 3 CGM sensor
 Software automatically
increases/decreases insulin
delivery to target a blood glucose
of 120 mg/dl
 Give bolus for meals
 Notify - exercise
Future Patch Pumps JewelPUMPTM
Debiotech Jewel
Micro-chip
7 day wear
500 IU of insulin
Clinical trials in France
(FDA application filed 2014?)
Patch Pumps
Cellnovo
France & UK
Medingo Solo Roche
(FDA approved in July 2009)
Valeritas V-Go
(FDA approved in Dec. 2010)
Preset basal rate to deliver 20, 30, or
40
Bolus dosing in 2 Unit increments up
to 36 Units
Calibra Finesse
(FDA approved in Jan. 2010)
Launch in 2016
200 units of insulin
Bolus only pump 1-2 units of Insulin / 0.5-5 unit boluses )
Insulin types
New Insulins/ Alternate
Routes of Insulin Delivery
• Viaject (in Phase III development) – works faster
than all existing insulins, mimics first-phase insulin
response
• Afrezza Technosphere inhaled insulin (MannKind) –
works like first-phase insulin response (FDA
approved – Adults)
• Oral-lyn buccal spray insulin
• SmartInsulin (SmartCells, Inc.)
• Insulin Patch (PassPort)
VIAject™
http://www.biodel.com/pipeline/viaject.htm
Inhaled insulin
AFREZZA®
Exubera
Smart insulin Patch
Microneedles
•
•
•
•
Glucose-responsive insulin.
Glucose sensing enzymes
Studied in animal models
Used for 9 hrs
Courtesy: Zhen Gu. Ph. D NC State University
2011
 U.S. Senators, Clinicians and People with
Type 1 Diabetes Urge FDA to Issue Clear
and Reasonable Guidance on Artificial
Pancreas
 In Just 23 Days, Over 100,000 Individuals
Sign Petition for the FDA to Advance,
Not Delay, the Development of an
Artificial Pancreas
Closed-Loop Systems – Hypoglycemia
Prevention
- Most of the severe hypoglycemic events occur at night 1
- 75% of hypoglycemic seizures in children 2
- 6% of the deaths (T1DM aged <40 yr) were due to “dead-inbed” syndrome 3
- Hypoglycemia occurred 8.5% of nights on open CGM 4
- 71% of youth didn’t respond to glucose sensor alarms during
the night 5
• Insulin + glucagon
• Bolus and then suspend basal
• Medtronic MiniMed 530G pump – auto-shutoff for lows (2
hour suspend) FDA approved
1 The DCCT , NEJM; 329(14):977-86,1993
2 Davis et al, Diabetes Care; 20(1):22-5,1997
3 Sovik and Thordarson, Diabetes Care; 22(l2):B40-2,1999
4 JDRF CGM Study group , Diabetes Care; 33:1004-8, 2010
5 Buckingham et al, Diabetes Technol Ther; 7:440-7,2005
Sensor Augmented Insulin Pumps
(SAP)
Medtronic MiniMed 530G
system
Animas Vibe system
)
Sensor-Augmented Pump Therapy
for A1C Reduction (STAR 3) Study
• 45% of SAP achieved HbA1c
targets
• 20% on MDIs
• HbA1C reduction of 1.2
percent
• No increase in the rate of
hypoglycemia
Slover RH at el. Effectiveness of sensor-augmented pump therapy in children and adolescents with type 1 diabetes in
the STAR 3 study. Pediatr Diabetes. 2012 Feb;13(1):6-11.
NEJM 2010– Medtronic sponsored trial
Counter regulatory delivery
Ilet –”Bionic Pancreas”
Bionic Pancreas – the iLet
Dual Chamber pump
Glucagon and Insulin Reservoir
http://sites.bu.edu/bionicpancreas/about-us/the-bionic-pancreas-ilet/
iLet – Carb entry feature
http://sites.bu.edu/bionicpancreas/about-us/the-bionic-pancreas-ilet/
Bi-hormonal pump CGMS - Case Study
The burden of diabetes: so much to
consider
What affects my diabetes
and what I need to know:
– Blood glucose
--HbA1c
– Food
– Activity
– Insulin
– Illness
– Stress level
What I need to carry:
– Insulin pump
– Blood glucose meter
– CGM
– Computer
– Internet access
– Mobile phone
– Instruction manuals
--Too much information!
-- Too many devices!
The burden of diabetes
Who needs to know about my diabetes?
– The hospital doctors
– PCP
– CDE/ diabetes nurses
– The dietitian
– The family
- School
– The pharmacy
– The pump supplier
Too many people!
Nightscout – CGM in the Cloud
 Allows real time access to a Dexcom G4 CGM from
web browsers via smartphones, computers, tablets,
and the Pebble smartwatch
 You can see your child’s real-time sensor readings
while they are away from you
 Requires cable, dedicated Android phone
 iPad, iPhone, Pebblewatch set-up info
OPEN APS
 The Open Artificial Pancreas System
project is an open and transparent effort
to make safe and effective basic Artificial
Pancreas System (APS) technology widely
available to more quickly improve and save
as many lives as possible and reduce the
burden of Type 1 diabetes.
OPEN APS
 Insulin pump and CGM
 Centralized controller - Raspberry Pi minicomputer
 USB or Bluetooth connection capability
 Translator device such as a Carelink USB
 Wireless Internet connection
OPEN APS /DoItYourself
 Parents/Friends/Patients – Coders/programmer
 Algorithms based on
 CGM
 Insulin on board
 Carbohydrate decay
 Calculated on active insulin
 Real-time predictive alerts for future high or low
BG states (hours in advance)
 Continually updated recommendations for
required insulin or carbs
http://diyps.org/
Have a app for that
•
•
•
•
•
•
•
Glooko Logbook - Free
dLife Diabetes Companion
MyNetDiary™
Moves
Ontrack
Glucose buddy
Insulincalc
Diasend
Glooko
Compatible with 50+ Meters, Insulin Pumps and CGMs, Paid service for patients
and HCP
Downloading and Interpreting
Data
Dexcom Clarity
Medtronic Carelink Personal
 Web-based
 PC and MAC compatible
 Uses Carelink USB or
Bayer Contour Link USB
 Sensor and Pump data
combined
 Can have data linked to
MD Office database
 Software downloaded from
website
 Iphone PC compatible
 Uses USB cable
 Sensor data
 Can email reports
Diasend, GlooKo, Tidepool
 Web-based
 PC and MAC compatible
 Use USB cable
 Sensor Data
 Can have linked to CHOC
database
TidePool – platform that will allow you to download all of your devices
to one place and view all of the data on one report
Animas, Asante, Dexcom, OmniPod, Tandem, and Abbott
 Developments in Type 2 Diabetes Mellitus
Traditional Oral Medications
 Metformin – Insulin Sensitizing agent
 Before starting metformin, obtain the patient’s eGFR.
 Contraindicated in patients with an eGFR below 30
 eGFR between 30 and 45 mL/minute/1.73 m2 is not
recommended.
 Obtain an eGFR at least annually
 Sulfonylureas - Stimulate insulin release
 Cardiovascular mortality was lower in those taking metformin vs
sulfonylureas.
Metformin-containing drugs: Drug safety communication - revised warnings for certain
patients with reduced kidney function [news release]. Silver Spring, MD: FDA; April 8,
Sodium Glucose Co transporter -2
SGLT2 inhibitors
 FDA warning regarding
increased Ketoacidosis
 Others





dehydration
kidney problems
Hypoglycemia
Increased cholesterol
Yeast infections
SGLT2 inhibitors
SGLT2 inhibitors lower blood sugar by causing the kidneys to remove sugar from
the body through the urine.
Generic
Brand name
Canagliflozin
Invokana
Canagliflozin and metformin
Invokamet
Dapagliflozin
Farxiga
Dapagliflozin and metformin extendedrelease
Xigduo XR
Empagliflozin
Jardiance
Empagliflozin and linagliptin
Glyxambi
Glucagon like peptides
GLP-1 agonists




Generic
Brand name
exenatide
Byetta/ Bydureon (ER)
liraglutide
Victoza, Saxenda (Obesity)
albiglutide
Tanzeum
dulaglutide
Trulicity
Stimulates insulin secretion
Inhibits glucagon secretion
Lowering blood sugar
Shorter-acting agonists
 lowering post-meal glucose spikes
 Long-acting
 Effect both post-meal and fasting glucose levels
GLP-1 agonists
 CI: MEN 2 SYNDROME
 Medullary thyroid carcinoma
 personal or family history




Pancreatitis
Gallbladder disease
Renal impairment
Suicidal thoughts
DPP-4 Inhibitors
Inhibits enzyme DPP-4
Increases GLP-1
Stimulates insulin production
Lowers glucagon
Generic
Brand Name
Alogliptin
Nesina
Linagliptin
Tradjenta
Saxagliptin
Ongglyza
Sitagliptin
Januvia
Increased risk of hospitalization for heart failure
TZDs




Generic Name
Brand Name
pioglitazone
Actos
rosiglitazone
Avandia
activate a protein PPAR g
decreasing insulin resistance.
Lower BG levels
Needs to monitor LFTs
Summary
 Immune therapies to slow or alter the autoimmune
process are Evolving
 Pump and Sensor technologies are evolving rapidly
 Closed loop systems will be leading the future
 Insulin only algorithms
 Insulin + Glucagon (bi-hormonal)
 Diabetes providers would need more exposure to newer
technologies
 Tech savvy parents or patients will be expecting more
from providers, drug & device manufacturers and FDA
 Type 2 Diabetes Mellitus – Much more treatment options
 In Pediatrics – Insulin & Metformin
Questions?